1. THE FUTURE OF CARDIOVASCULAR BIOMARKERS : FROM RISK STRATIFICATION TO PRECISION MEDICINE

A Critical Mechanisms Of Disease (CMOD) – CVCT joint session

Chairpersons: TBD

High sensitivity troponins are useful for diagnosis and prognosis in patients with suspected acute coronary syndrome. Though a large volume of evidence to support their utility in such settings has been generated, there is a lack of consensus on the optimal way in which to apply these assays in clinical practice. Novel, rapid algorithms may hold the key to improved patient care using these biomarkers, but much remains to be discussed.

Recent publications have focused the attention of many clinicians on the potential role for biomarkers of cardiac injury in refining the approach to cardiovascular (CV) risk stratification in the general population. Whether this will ultimately change practice remains to be seen.

Biomarkers may serve to discriminate various substrates for coronary syndromes and heart failure that could direct individuals to different management strategies. As such, they may stratify patients mechanistically and therapeutically and might help achieve the goal of a more precision management and personalized approach.

Whether these concepts has gained power and how much are these pertinent to precision and personalized medicine, and how to incorporate in future CV trials is a matter of intense debate.

Lessons learnt from the mixed success of biomarker – guided clinical trials need to be shared with the aim of refining methodology and moving the area forward.

Keynote lecture:

Circulating and imaging biomarkers of atherosclerosis and prospects of precision management and personalized approach of cardiovascular disease.

Peter Libby (Boston, USA)

Is CV risk modified by therapies and can that be monitored using CV biomarkers?

Nick Mills (Edinburgh, GBR)

The role of biomarkers in detecting risk of cardiac toxicity in cancer trials.

Jean Claude Tardif (Montreal, CAN)

Can high sensitive troponins improve cardiovascular risk stratification in the general population?

In EU: Stefan Blankenberg (Hamburg, GER)

In US: Christie Ballantyne (Houston, USA)

In Women: Carolyn Lam (Singapore, SGP)

Risk stratification of suspected ACS patients: Optimal algorithm and Point of Care devices?

2. EXPANDING THE INDICATIONS OF NOACs. DISSECTION OF THE COMPASS TRIAL IN PATIENTS WITH CORONARY AND/OR PERIPHERAL ARTERY DISEASE

Chairpersons: TBD

Peripheral artery disease (PAD) is considered to be a clinical manifestation of systemic atherosclerosis. Most patients presenting with peripheral artery disease are at high risk for myocardial infarction, ischemic stroke, and cardiovascular death. Concomitant clinical evidence of coronary magnifies this risk.

Antiplatelet therapy and statins, are the cornerstone of care for the prevention of atherosclerotic events. However, the level of evidence in favor of aspirin in PAD is modest and is mainly based on a meta-analysis involving approximately 5000 patients. In two large clinical trials, in patients with asymptomatic atherosclerosis (which was defined as an abnormal ABI value) aspirin was not superior to placebo in preventing cardiovascular events.

In the CAPRIE trial, in a broadly defined stable population of patients with atherosclerotic disease, including coronary artery disease, peripheral artery disease, and cerebrovascular disease, clopidogrel was superior to aspirin. Benefit was driven mainly by the subgroup of patients with PAD. These results from CAPRIE established clopidogrel as the first therapy for peripheral artery disease to be approved by the Food and Drug Administration.

The CHARISMA trial, enrolling similar high-risk population of patients with atherosclerosis found no significant benefit for clopidogrel over aspirin in the risk of cardiovascular events in the overall population. However, there was a non-significant trend in the subgroup of patients with PAD. Dual antiplatelet therapy was associated with an increased risk of bleeding. On the basis of this evidence, clopidogrel monotherapy has been the preferred therapy to manage the atherothrombotic risk in patients with peripheral artery disease.

In patients with symptomatic PAD enrolled in the EUCLID trial, ticagrelor was not superior to clopidogrel for the reduction of cardiovascular events, and each drug was associated with similar rates of major bleeding.

The COMPASS trial randomized 27,402 patients with coronary artery disease or peripheral artery disease (PAD) to receive the oral anticoagulant rivaroxaban at 2.5 mg twice daily plus aspirin at 100 mg/day, or rivaroxaban 5 mg twice daily without aspirin, or aspirin 100 mg/day without rivaroxaban. The trial was stopped prematurely more than a year ahead of its planned March 2018 completion because, in an interim analysis, the primary end point of MI, stroke, or cardiovascular death "has reached its pre-specified criteria for superiority."

COMPASS, Design, highlights of major results

Target patient population. To what patient do the COMPASS results apply?

Cardiovascular death is either the leading or one of the main causes of death in patients with chronic kidney disease (CKD).

CKD is one of the main features associated with poor outcomes in cardiovascular disease patients, especially those with heart failure and/or diabetes.

The most suitable choice of components of the composite endpoint for a cardiovascular outcome trial conducted specifically in the CKD population is obviously key for success and depends on the specific therapy being tested.

Renal endpoints are pathophysiologically relevant in a CKD population even if the primary intervention target is cardiovascular disease, and a composite endpoint reflecting both cardiovascular and renal outcomes may be desirable, especially if the intervention is expected to affect both systems.

However, a challenging problem is which endpoints to combine and how to interpret the results of the composite endpoint.

Moreover the meaning of a worsening renal function may be different depending on the considered setting (acutely decompensated heart failure vs. chronic, renin angiotensin aldosterone system inhibition (RAASi) use and uptitration, biphasic temporal effect of SGLT2 inhibition on kidney function…).

One may also wonder if changes in estimated glomerular filtration rate and/or microalbuminuria should be considered as relevant biotargets and surrogates of outcomes whilst assessing the cardiovascular benefit of a new compound and if any, which outcome (cardiovascular or renal) should be prioritized for testing if the compound exhibits cardiorenal effects.

Finally, should we pay attention to a worsening in renal function under RAASi as long as potassium concentrations are maintained in the normal range with a potassium binder?

Changes in GFR: How to assess? Reversible vs. irreversible, short – term vs. long-term, and when are these good news, neutral news, or bad news?

Investigator viewpoints:

Claudio Ronco (Vicenza, ITA)

Michael Felker (Durham, USA)

The Issue with competing risk and composite endpoints

TBD

Regulatory viewpoint:

Aliza Thompson (FDA, USA), Angeles Alonso (EMA, GBR).

Industry perspective: TBD

Definitions of 'Worsening Renal Function' in cardiorenal trials. How to balance sensitivity and specificity?

Javed Butler (New York, USA)

Patrick Rossignol (Nancy, FRA)

Should renal function ever be a primary efficacy endpoint or only a safety endpoint in heart failure?

HFrEF vs. HFpEF

Scott Solomon (Boston, USA)

Acute HF

Alexandre Mebazaa (Paris, FRA)

Nephrologist viewpoint

George Bakris (Chicago, USA)

Renal endpoints in the setting of CV prevention trials

Hypertension

William Cushman (Memphis, USA)

Diabete

TBD

Diabetes Kidney Disease

FIGARO – FIDELIO

Rajiv Agarwal (Indianapolis, USA)

CREDENCE

Vlado Petrovic (Sydney, AUS)

Regulatory viewpoint:

TBD (FDA, USA), TBD (EMA, XXX).

Industry perspective:

TBD

Patients’ perspective:

Cynthia Chauhan (Wichita, USA)

THE FORUM

Moderated discussion with the audience

Chairpersons: TBD

Panelists: All speakers

4. TRANSCATHETER HEART VALVE THERAPIES TRIALS

Chairpersons: Robert Bonow (Chicago, USA)

Could THV device approval follow a pathway analogous to that of surgical heart valves by incorporating OPC? Would this be more appropriate only for approval of new-generation THVs in high- and extreme-risk patient populations?

Should approval of THV devices for low- and intermediate-risk patients or for new indications be based on data from randomized, clinical trials?

How contemporary registries may be useful as a platform for regulatory reform of cardiovascular devices, for generating data to serve as a comparator arm for future trials and to establish objective performance criteria? To perform comprehensive, reliable, and timely post-marketing safety surveillance

This session aims at discussing the current state of the use of digital technology and mobile health in clinical trials in cardiovascular medicine, what data is available for utilizing digital technology as a supportive tool or an intervention in clinical trials, and how can digital technology be used to streamline clinical trial conduct (reduce visits, enrollment/recruitment, subject retention, safety data collection, “site-less” remote clinical trials).

Potential outcomes (ex. PRO, HR/BP, and activity trackers) can be used with digital health. Can these be used for new drug registration trials and/or post-marketing trials?

Experts in large IT data platforms will present case studies and discuss what can be gained in CV clinical trial conduct and what are the barriers/challenges to utilizing digital technology in global CV clinical trials.

6. EVOLVING APPROACH TO THE CONDUCT OF CARDIOVASCULAR AND RENAL OUTCOME TRIALS IN DIABETES. HOW DO RECENT TRIALS INFORM FUTURE DRUG DEVELOPMENT?

Regulatory agencies state that reduction of glycated haemoglobin (HbA1C) is an appropriate primary endpoint in diabetes drug development, as it reflects glucose control, and is known to be correlated with a reduced risk of micro vascular complications.

Until recently, data have not supported a beneficial effect of improving glycaemia in diabetes on CV outcomes. Beneficial effects on macro-vascular complications can only be evaluated properly in large scale and long-term controlled clinical trials, which are not considered mandatory for marketing authorisation approval.

In case it is considered necessary to perform a more in depth assessment of the cardiovascular safety profile of a new drug intended for the treatment of diabetes, EMA recommends two approaches: a meta-analytic approach of outcome data generated in the phase II/III studies, or a dedicated cardiovascular outcome study.

The FDA guidance recommends a dedicated preapproval CV trial powered to establish safety by establishing an upper bound of the two-sided 95% confidence interval below 1.8 with the requirement for a subsequent trial to establish non-inferiority to rule out an upper bound confidence interval exceeding 1.3 for a new drug intended for the treatment of diabetes.

Would a more tailored approach, requiring a CVOT depending on the mechanism of action of a specific drug and based on nonclinical and early phase clinical data be more appropriate?

The EMA’s and FDA’s preferred safety endpoint, is a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Heart failure events occur with a similar frequency as myocardial infarction and with a greater frequency than stroke in patients with type 2 diabetes mellitus at high cardiovascular risk. Regulatory agencies should recommend including heart failure events as endpoints in diabetes clinical trials, whether evaluating efficacy or safety. Should only heart failure requiring hospitalization be the CHF endpoint? Should the focus on primary endpoint (3pt MACE vs CHF) be a function of the mechanism of action of the drug under development?

Trials set in compliance with this guidance have occasionally been powered for efficacy, or efficacy has been tested as part of the statistical hierarchy after CV safety has been established. If efficacy (superiority over standard of care) has been established in a trial (as for empagliflozin, liraglutide, and semaglutide), does this have the same strength of evidence as a trial designed for superiority? Should criteria for establishing CV efficacy based on a single trial be explicitly described and, if so, what is an appropriate p value for superiority?

Trials using agents from the same pharmacological classes produced discrepant results (LEADER and SUSTAIN6 vs. ELIXA and EXSCEL; SAVOR vs. other DPPIV trials; EMPA-REG vs. CANVAS raising issues about class effect vs structural/pharmacokinetic differences between molecules of the same class.

There are emerging data suggesting an association between severe hypoglycaemia and death, which should be taken into account in differentiating among new drugs intended for the treatment of diabetes.

Endpoint related issues

Non-inferiority safety endpoints should no longer be the rule for new drugs intended for the treatment of diabetes Are efficacy endpoint trials always preferable.

TBD

What is the place for glycemic-related endpoints (HbA1c) in diabetes trials?

Payers’ viewpoint: How to value a diabetes drug with CV mortality benefit?

TBD

The Forum. Moderated discussion with the audience

Refining the current regulatory guidance.

Chairpersons: TBD

Panelists: All speakes

7. ONGOING AND FUTURE ATHEROSCLEROSIS TRIALS

Chairpersons: TBD

Residual risk still represents an important issue in patients with manifest cardiovascular disease. Thus, over 5 years post-ACS still 20% of patients have died.

Several additional strategies have been reported this year or are presently being tested in large clinical trials like aggressive lowering of LDL cholesterol by PCSK9 inhibition or an RNA silencing mechanism, lowering of Lp-a and finally triglycerides (TG) have seen a revival and their lowering is presently being tested in several trials applying different interventions like high-dose omega-3 and 6 or a SPARM (selective PPARα modulator). But novel strategies are at the horizon.

The recently published FOURIER Study has shown a 20% decrease of a combined endpoint consisting of cardiovascular death, MI and stroke in stable patients with manifest atherosclerosis and an index event that had occurred 3 years before randomization. These results fit very nicely in the cholesterol trialists estimation but are somewhat lower as suggested by two back to back published reports from the PROFICIO and the ODYSSEY program in 2015. Despite having reached on treatment LDL levels of 30 mg/dl there was a significant number of patients with recurrent events, which is in line with 36% of patients showing progression in the previously published GLAGOV IVUS Trial also with evolocumab. Thus, there is room for other pathomechanisms and anti-inflammatory treatment on top of standard of care might represent an alternative. During ESC this year the CANTOS trial in which 10,000 post ACS patients were treated with an interleukin-1β antagonist will be presented and we then will know whether or not the inflammation hypothesis is true or has to be rejected. If CANTOS is positive this may implicate a paradigm change in the treatment of patients with manifest atherosclerosis.

PCSK9 Trials

PCSK9: From discovery to clinical evidence

TBD

FOURIER: enough evidence to justify widespread use? Did it fulfill its expectations?

Marc Sabatine (Boston, USA)

SPIRE: an excursion into immunology

Speaker: Jean Claude Tardiff (Montreal, CAN)

Discussant: Ira Tabas (New York, USA)

ORION 1: Impressive results leading to ORION Outcome

TBD

Trials of agents targeting inflammation

Update of inflammation in atherosclerosis

Speaker: TBD

Discussant: TBD

CANTOS: Anti-inflammatory treatment in the context of extreme low LDL levels. Is there still room for improvement?

TBD

Lessons fro COLCOT and other ongoing and future nti-inflammatory trials

Jean Claude Tardif (Montreal, CAN)

Further insights regarding into triglycerides as a target for intervention:

Payers viewpoint: How much PCSK9 inhibition can the health care system afford?

Christian Thuillez (HAS, Rouen, FRA)

Patient viewpoint: TBD

The Forum. Moderated discussion with the audience

Chairpersons: TBD

Panelists: All speakers

8. ATRIAL FIBRILLATION TRIALS. A HRS – CVCT joint session

hairpersons : George Van Hare (Saint Louis, USA), TBD

Ablation trials

Current guidelines recommend pulmonary-vein isolation by means of catheter ablation as treatment for drug-refractory paroxysmal atrial fibrillation. Radiofrequency ablation is the most common method, and cryoballoon ablation is the second most frequently used technology.

It was recently reported that cryoballoon ablation was noninferior to radiofrequency ablation with respect to efficacy for the treatment of patients with drug-refractory paroxysmal atrial fibrillation, and there was no significant difference between the two methods with regard to overall safety. (FIRE AND ICE).

It is not known whether successful ablation of AF, regardless of technique, will result in reduced mortality. This is under investigation in the Catheter Ablation versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) and Catheter Ablation versus Standard Conventional Treatment in Patients With LV Dysfunction and AF (CASTLE-AF)

However, specifically in persistent atrial fibrillation in patients with heart failure catheter ablation, whether ablation is superior to amiodarone was examined in a randomized study which showed that catheter ablation of atrial fibrillation is superior to amiodarone in achieving freedom from AF at long-term follow-up and reducing unplanned hospitalization and mortality in patients with heart failure and persistent AF.

NOAC trials

Trials reporting anticoagulant benefits in AF were done in people with either symptomatic AF or paroxysmal AF long enough to be recorded on multiple ECGs.

Diagnosis of short term AF is of uncertain significance. It seems that only longer-lasting AF associates with stroke.

How valuable short-duration AF as a surrogate marker is questionable and needs further substantiation.

Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary intervention (PCI) among patients with atrial fibrillation (AF) rely on retrospective, nonrandomized observational data. Currently, patients are treated with triple-therapy (dual antiplatelet therapy [DAPT] + oral anticoagulation therapy), but neither the duration of DAPT nor the level of anticoagulation has been studied in a randomized fashion. Recent studies also suggest dual pathway therapy with clopidogrel plus oral anticoagulation therapy may be superior, and other studies suggest that novel oral anticoagulants such as rivaroxaban may further improve patient outcomes. The PIONEER AF-PCI study is the first randomized comparison of VKA vs. novel oral anticoagulant therapy in patients with AF receiving antiplatelet therapy after PCI to assess the relative risks of bleeding complications.

Left atrial appendage closure trials

After the initial trials and within the context of controversial evidence of efficacy of the FDA approved Watchman percutaneous left atrial appendage closure (LAAC), further data are derived from registries. CMS covers FDA approved LAAC for non-valvular atrial fibrillation through Coverage with Evidence Development (CED) in patients enrolled in certain well designed registries and in FDA approved trials. Patients unsuitable for oral anticoagulation are further evaluated with in the ASAP-TOO trial

Research on the causes and mechanisms of AF points to the role of fibrosis. Trials of anti fibrotic agents?

The current state of atrial fibrillation prevention and treatment trials

Cecilia Linde (Stockholm, SWE)

Atrial fibrillation catheter ablation. Are we generating the needed evidence?

So-called “neutral” or “negative” trials contribute to the body of evidence with a drug, device, or procedure. Such trials often provide relevant knowledge to the field and often inform planning of subsequent randomized trials.

When a trial fails to show statistically significant evidence of benefit of an experimental intervention, the cardiovascular community should ask whether the intervention worked, but the trial was flawed in some way, or the trial was valid but the intervention was ineffective.

The appropriate next steps after completion of an inconclusive trial are influenced by 1) whether a strong mechanistic or biologic rationale supports use of the treatment and 2) the overall assessment of potential reasons why the trial did not meet its primary objective.

It is crucial, but often difficult, to determine if a clinical outcomes trial did not show a treatment effect because of errors in trial design or execution or if the treatment was truly ineffective.

“Autopsy is performed by anatomists with the principal aim of an autopsy is to determine the cause of death, the state of health of the person before he or she died, and whether any medical diagnosis and treatment before death was appropriate.”

The objective of this session is to have trial specialists examine failed trials with the aim of determining causes of failure, the robustness of the trials before they failed, and whether any appropriate early examination or corrective action could have prevented negative/neutral results.

The aim is ultimately to draw lessons that may inform the design and the conduct of future trials. Future trials may be designed addressing lessons learned from informative but inconclusive trials, applying different patient populations, alternate treatment regimens, or different outcomes. Alternatively, trials should be viewed in the broader context of how the results can inform the field.

Regulators and payers sometimes differ in their perspectives on medical advances and the weight they place on components of the evidence base. These contrasting priorities can lead to divergence between regulatory and payer decisions and delays or barriers in patients’ access to new therapies.

Those involved in coverage decisions have not routinely been integrated in the drug development process pre-approval, specifically with respect to clinical trial design. Inclusion of payer representatives sooner in the development process would provide opportunities to detect discordance among stakeholders in terms of data priorities, facilitate cooperation to align objectives, agree on the evidence required for approval and reimbursement, improve transparency and accountability of payer decision making, and ideally minimize delays in patient access to new therapies.

“Value-based healthcare”, focuses on outcomes that are relevant to patients, including, but not limited to, clinical outcomes

Therefore a linked or network of evidence approach may be better suited to device evaluations than a ‘hierarchy of evidence’ approach.

Health ministers in EU recently mandated that the OECD develop an instrument to collect information (PaRIS) to be able to compare the performance of health systems, as well as the performance of clinicians and technology.

MedTech companies and organizations in Europe and the USA currently has programs in place to drive “value-based healthcare”

Device evaluations are enhanced when device developers, manufacturers, trialists, regulators, payers, health professionals and patients collaborate to agree on the “Burden of proof” and describe at an early stage the potential mechanisms/pathways through which achieve “value-based healthcare”, ultimately improving timely patient access to new treatments that reduce the burden of disease or prolong life.

Panel on Evaluation Systems for New Technology: Overview & comparison of evaluation systems. Discussion on whether certain evaluation systems are better suited for certain types of devices/ disease states/ healthcare system. Identification of one evaluation system that is preferred over others.

From “evidence-based” to “value-based” healthcare: The rationale behind this global trend

Karl Moons (Utrecht, NED)

Medicare Evaluation: What is the process & what evidence is required for coverage today?

Pay-for-performance: What is the framework & which health systems manage it best?

TBD

Panel on Streamlining Clinical Trial Data Collection with Evaluation System Requirements: Overview & comparison of relevant types of clinical data, with a focus on how each serves (or does not serve!) one of the respective evaluation systems. Discussion on why and how evaluation systems must evolve to take such critical data into account.

11. WHY SOME CLINICAL TRIALS DO NOT WORK OR HAVE AN IMPACT:
ARE THERE WAYS TO DO A BETTER JOB?

Chairpersons: TBD

The structure of a large international clinical trial is complex. It typically involves a sponsor, a leadership committee, numerous geographically-dispersed investigators, and a group responsible for operational functions.

A pharmaceutical executive or academic leader must decide whether to propose a very large expensive clinical trial to upper management. The data supporting the drug is marginal. He/she advocate strongly for investment, emphasizing data that are hopeful but minimizing risks.

The leadership committee defines the trial hypotheses and the methods by which the hypotheses can be tested in an unbiased manner. Members focus on the big picture, but do they really know how the trial is being executed?

Most sponsors lack internal resources to execute the trial and thus seek help from an outside vendor, a CRO. Their procurement office provides the contract to the lowest bidder.

The CRO is itself a business enterprise, which has a responsibility to carry out the trial in a manner financially advantageous to its owners or shareholders. They identify investigators who can recruit quickly and inexpensively.

The investigators are paid to recruit patients. Some are very creative in enrolling patients very quickly. When the trial is over, they will receive little academic credit, but will rapidly move on to the next trial.

The operations group is charged with ensuring that patients are recruited into the trial on schedule and that the data quality can be made to appear to be reasonable.

The data are collected, but the analysis unit understands that certain results will yield predictable benefits. If this is a phase II trial, a trial yielding positive results is likely to be followed by additional substantial investment in more studies.

If this is a phase III trial, the results are rarely satisfying; i.e., the trial’s primary hypothesis has proven to be valid, and the supporting data are of very high quality. Much more often than not, both the leadership committee and the sponsor are disappointed by the results. There may be some positive signals, but one can find them only after a very diligent and creative search.

The results of the trial are presented, and internet scavengers emerge from their hiding places to feast. If the trial is markedly positive, these vultures seek perceived flaws or hold the trial’s conduct to unrealistic standards. If not, they demand replication (even if it is unethical or not feasible). If the results are disappointing, they rejoice in their claims that they predicted the trial’s failure.

The results of the trial are published. How should a new study be interpreted? Many physicians do not even make an attempt to read and understand the primary publication; often they wait for the chatter on the internet or official guidelines to tell them what to do. Physicians have insufficient knowledge, time or motivation to perform a proper evaluation.

An overview of the problem

Milton Packer (Dallas, USA)

How do sponsors make a decision to support a trial?

Ameet Nathwani (Sanofi, FRA)

Can academic leaders oversell an idea?

Gabriel Steg (Paris, FRA)

Who should be minding the store?

Janet Wittes (Statistics Collaborative, USA)

Why do I sometimes have trouble sleeping at night?

TBD

Why is the academic investigator becoming extinct?

TBD

Which types of investigative sites do regulators worry about?

Norman Stockbridge (FDA, USA)

TBD (EMA, xxx)

Are practitioners paying any attention to the results of trials?

TBD

What do journal editors think of professional cynics?

Stuart Spencer (The Lancet, London, GBR)

John Jarcho (NEJM, Boston, USA)

Are payors happy when a trial shows a benefit of an expensive drug?

Tamara Sysek Jensen (CMS, USA), TBD (Europe)

THE FORUM

Moderated discussion with the audience

Chairpersons: TBD

Panelists: All speakers

12. TIME IS MUSCLE. ACUTE INTERVENTION TRIALS

Chairpersons: TBA

Advances and remaining gaps in the early management of acute coronary syndromes